DESCRIPTION: Human parainfluenza virus type 3 (HPF3), a member of the paramyxovirus family of non-segmented negative-strand RNA viruses, is an important agent of lower respiratory tract disease in children and causes several of the most significant childhood viral diseases (croup, bronchiolitis and pneumonia). The recognition of infections caused by HPF3 is increasing in the U.S. due to the increasing numbers of individuals with underlying immune deficiencies, and serious HPF3 disease is re-emerging. There are currently no treatments or vaccines available to combat this serious pediatric pathogen, and there remain gaps in the knowledge of fundamental processes leading to growth of the virus. Dr. Moscona's studies have provided an understanding of some factors controlling virus-host cell interactions for HPF3, including the role of HN in the virus-induced fusion process. The overall goal of the current proposal is to expand the investigation of the molecular pathogenesis of HPF3. The central hypothesis is that the envelope glycoprotein hemagglutinin-neuraminidase (HN)-receptor interaction is critical for several essential components of the viral life cycle -- entry, fusion and release -- and that this interaction regulates pathogenicity in vitro and in vivo. The specific objectives of the current proposal are: (1) To elucidate both the viral HN and cellular receptor components of the virus-host interaction, specifically by (A) evaluating the role of HN in viral entry, fusion and release using HPF3 HN variants that are altered in receptor binding or fusion promotion and (B) identifying functional cellular receptor molecules for HN. (2) To evaluate strategies for interfering with HN-receptor interaction and thus test the hypothesis about the functions of HN in the viral life cycle, using (A) sialic acid analogs that mimic the sugar moiety of the HN receptor as decoys to interfere with viral attachment and (B) HN expression on the surface of uninfected cells to mimic viral interference and thus prevent viral entry. (3) To analyze the contribution of the HN-receptor interaction to pathogenesis in vivo by extending the studies to HPF3 infection in the cotton rat, a model that mimics HPF3 lower respiratory tract infection in man. She will test the hypotheses that (A) avidity of virus-receptor interaction is a determinant of pathogenesis in the lung and (B) neuraminidase determines the outcome of infection in the lung as it does in cell culture.